Hepatitis C virus (HCV) infection is a major health problem that leads to chronic liver disease, such as cirrhosis and hepatocellular carcinoma, in a substantial number of infected individuals. Current treatments for HCV infection include immunotherapy with recombinant interferon-α alone or in combination with the nucleoside analog ribavirin.
Several virally-encoded enzymes are putative targets for therapeutic intervention, including a metalloprotease (NS2-3), a serine protease (NS3, amino acid residues 1-180), a helicase (NS3, full length), an NS3 protease cofactor (NS4A), a membrane protein (NS4B), a zinc metalloprotein (NS5A) and an RNA-dependent RNA polymerase (NS5B). The NS3 protease is located in the N-terminal domain of the NS3 protein, and is considered a prime drug target because it is responsible for an intramolecular cleavage at the NS3/4A site and for downstream intermolecular processing at the NS4A/4B, NS4B/5A and NS5A/5B junctions.
The compounds that can be prepared by the processes of this disclosure are effective as inhibitors of intermolecular cleavage at the NS3/4A site (referred to herein as “HCV NS3 inhibitors” or “HCV NS3 inhibitor compounds”). Such compounds are therefore useful in the treatment of hepatitis C viral infection and conditions caused by HCV. International Patent Application Publication WO2007/015855 and International Patent Application Publication WO2007/015787 describe macrocyclic compounds that are useful as HCV NS3 inhibitors and useful in the treatment of HCV and conditions caused by HCV infection. There is, therefore, a need for chemical processes for preparing compounds that are potent inhibitors of intermolecular cleavage at the NS3/4A site. This disclosure addresses this need.